PROJECT SUMMARY Trastuzumab, a monoclonal directed against the human epidermal growth factor (EGF) receptor-2 (HER-2), revolutionized HER-2-positive breast cancer treatment, albeit, with the therapy-limiting side effect of cardiotoxicity. We found that 40% of patients experience a left ventricular ejection fraction (LVEF) decline >10% during trastuzumab therapy, and 4% develop heart failure (HF). In 25-50% of these cases, the LVEF decline is not fully reversible, even with cardiovascular therapy. Genetic contributors to cardiac vulnerability and the best cardiovascular management strategy are unknown. A critical need exists for cardio-preventive approaches in patients at risk of trastuzumab-induced cardiotoxicity. The current application?s objective is to evaluate cardio-protective approaches using carvedilol in curative-intent trastuzumab for HER-2-positive breast cancer. Our central hypotheses are that a pre-emptive preventive approach (cardiovascular therapy with the beta-blocker carvedilol started before trastuzumab therapy), or a reactive preventive approach (cardiovascular therapy started in response to early subclinical signs of cardiac dysfunction/ injury, i.e. cardiac troponin elevation or abnormal global longitudinal strain (GLS)) will reduce cardiotoxicity compared with a standard ?wait-and-see? approach (carvedilol prescribed once cardiotoxicity has occured). We furthermore hypothesize that carvedilol extension beyond the active trastuzumab treatment leads to superior outcomes and that pharmacogenomics can predict cardiotoxicity non-responsive to cardiovascular therapy with carvedilol. This clinical trial will test these hypotheses, involving 450 adult breast cancer patients beginning a year of curative-intent trastuzumab therapy, randomized to either a preemptive, a reactive, or reference care approach. This study addresses three specific study aims: Aim 1: To compare the incidence of a) HF or asymptomatic decline in LVEF by >10% in those with LVEF ?50% or ?5% in those with LVEF decrease to a nadir of <50% (lead primary aim #1), and b) reversible LVEF decline to within 5% of baseline (secondary primary aim #1) with a pre-emptive, reactive, and ?wait-and-see? approach of carvedilol initiation in breast cancer patients over the course of adjuvant trastuzumab therapy. This aim addresses the question of initiation of cardioprotective efforts for trastuzumab therapy. Aim 2: To compare the delta change in LVEF from completion to 1 year post-completion of trastuzumab therapy between a cardioprotective approach with carvedilol confined the duration of trastuzumab therapy or extended for 1 year thereafter. This aim addresses the question of duration of cardioprotective efforts for trastuzumab therapy. Aim 3: To test the association of predefined genetic variants with change in GLS and LVEF during and after trastuzumab therapy, adjusted for treatment arm. This aim is to identify genetic variants that predict trastuzumab cardiotoxicity in general as well as lack of response (primary prevention of drop in LVEF or secondary improvement of LVEF) to carvedilol. This trial?s completion will guide clinical care in seeking the best management strategy (?tactic?) for cardio-protection in breast cancer patients undergoing trastuzumab therapy in terms of efficacy, time of initiation, and duration of treatment with the beta-blocker carvedilol.